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Liver receptor homolog 1 controls the expression of the scavenger receptor class B type I.

ABSTRACT: The scavenger receptor class B type I (SR-BI), which mediates selective cellular cholesterol uptake from high-density lipoproteins (HDLs), plays a key role in reverse cholesterol transport. The orphan nuclear receptor liver receptor homolog 1 (LRH-1) and SR-BI are co-expressed in liver and ovary, suggesting that LRH-1 might control the expression of SR-BI in these tissues. LRH-1 induces human and mouse SR-BI promoter activity by binding to an LRH-1 response element in the promoter. Retroviral expression of LRH-1 robustly induces SR-BI, an effect associated with histone H3 acetylation on the SR-BI promoter. The decrease in SR-BI mRNA levels in livers of LRH-1(+/-) animals provides in vivo evidence that LRH-1 regulates SR-BI expression. Our data demonstrate that SR-BI is an LRH-1 target gene and underscore the pivotal role of LRH-1 in reverse cholesterol transport.

SUBMITTER: Schoonjans K

PROVIDER: S-EPMC1308324 | biostudies-literature | 2002 Dec

REPOSITORIES: biostudies-literature

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Liver receptor homolog 1 controls the expression of the scavenger receptor class B type I.

Schoonjans Kristina K Annicotte Jean-Sebastien JS Huby Thierry T Botrugno Oronza A OA Fayard Elisabeth E Ueda Yukihiko Y Chapman John J Auwerx Johan J

EMBO reports 20021121 12

The scavenger receptor class B type I (SR-BI), which mediates selective cellular cholesterol uptake from high-density lipoproteins (HDLs), plays a key role in reverse cholesterol transport. The orphan nuclear receptor liver receptor homolog 1 (LRH-1) and SR-BI are co-expressed in liver and ovary, suggesting that LRH-1 might control the expression of SR-BI in these tissues. LRH-1 induces human and mouse SR-BI promoter activity by binding to an LRH-1 response element in the promoter. Retroviral ex ...[more]

PMID: 12446566

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Project description:BackgroundScavenger receptor class B type I (SR-BI) plays a key role in high density lipoproteins (HDL) metabolism. SR-BI deficiency in mice results in enhanced susceptibility to atherosclerosis with abnormal large, cholesterol enriched, and functional impaired HDL. This study was to characterize the protein markers of dysfunctional HDL in SR-BI deficient (SR-BI-/-) mice and to test if the defective of HDL might be affected by probucol treatment.MethodsShotgun proteomics and 2-D gel electrophoresis were performed to examine the profile of HDL protein and distribution of HDL particles isolated from SR-BI-/- mice. HDL's cell-function, paraoxonase 1 (PON1) and myeloperoxidase activity were assessed. The mice were treated with 1.2 mg/g/day probucol for 6 weeks and the impact on HDL protein markers was analyzed. The differential proteins were quantified by Western blotting.ResultsThe relative amount of protein in SR-BI-/- HDL was decreased by about 25% compared to that in HDL from wild type (WT) mice. Compared to WT HDL, relative protein abundance of representative apoAI and PON1 in SR-BI-/- HDL were significantly reduced, whereas acute-phase protein serum amyloid A (SAA) and apoAIV, proteinase inhibitor proteins ?-1-antitrypsin (A1AT) were increased. The distribution of plasma apoAI-containing HDL particles in SR-BI-/- mice was also dramatically altered, although plasma apoAI level was no difference. The protein alterations were accompanied with dysfunction of SR-BI-/- HDL, evidenced by impaired cholesterol homeostasis in macrophages, and reduced anti-oxidative and anti-inflammatory effects. Probucol treatment of SR-BI-/- mice could restored the relative contents of critical proteins including apoAI, PON1, SAA, apoAIV and A1AT on HDL, and improve HDL dysfunction despite decreased HDL-C level.ConclusionSR-BI deficiency leading to dysfunctional HDL is closely related to alteration of HDL protein, suggesting that identification of apoAI, PON1, SAA, apoAIV, and A1AT may serve as the valuable protein markers for diagnosis and therapeutics of dysfunctional HDL-related metabolic diseases.

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Liver receptor homolog 1 controls the expression of the scavenger receptor class B type I.

Publications

Liver receptor homolog 1 controls the expression of the scavenger receptor class B type I.

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